For several years our primary research interest has focused on the regulation of protein synthesis in reticulocyte lysates. This system synthesizes globin chains with an efficiency that approaches in vivo rates. More significantly, globin synthesis is completely dependent upon the addition of hemin. In the absence of hemin, there is an abrupt cessation of synthesis due to the activation of a heme-regulated inhibitor. The inhibitor has been purified 5,000-fold to near homogeneity, and has been identified as a cAMP-independent protein kinase which specifically phosphorylates the small polypeptide component (38,000 daltons) of the initiation factors eIF2. This factor mediates the binding of initiator methionyl-tRNA to the 40S ribosomal subunit. Similar protein kinase activities and inhibitions are induced by double-stranded RNA (dsRNA) and oxidized glutathione (GSSG). The conclusion that eIF2 is the target of all three inhibitory modes is strongly supported by the finding the exogenous eIF2 overcomes all three inhibitory modes is strongly supported by the finding that exogenous eIF2 overcomes all three inhibitions. The observation that similar translational controls are present in non-erythroid cells such as rat liver and Ehrlich ascites tumor cells, indicates that these regulatory mechanisms may be widespread. Recent evidence suggests a number of physiological events give rise to similar protein kinase activities and corresponding inhibitions of protein chain initiations. Among these are glucose deprivation, amino acid starvation, elevated temperatures, anaerobiosis, hypertonic shock, and certain types of anemia. In all of those systems which have been examined, there appears to be a correlation between the phosphorylation of eIF2 and the inhibition of protein synthesis, a phenomenon which emphasizes the importance of this control mechanism. The emphasis of current research efforts is focused on two objectives: a. the purification and molecular relationship of the inhibitors induced by heme-deficiency, dsRNA, and GSSG; and b. the regulatory function of these inhibitors in vivo.